Drugs, Neurochemistry and Transmission of Nervous Systems

Question 1

What are the fundamental principles of chemical neurotransmission at a synapse?

Answer 1

1. Synthesis of NT
2. Storage of NT
3. Release of NT
4. Reuptake of NT
5. Metabolism of NT
6. Receptor Interaction

Question 2

What percentage of NA in synaptic clefts is reuptaken and recycled?

Answer 2

Approximatley 90-95% of synaptic NA is recycled - all most of it neuronally reuptaken and a small portion taken up extraneuronally (e.g. by glial cells)

Question 3

NA regulatory feedback is achieved pre-synaptically via what type of receptor?

Answer 3

a2 adrenoceptors

Question 4

What are monamine oxidases and catechol-o-methyltransferases (COMT)?

Answer 4

Monoamine Oxidases (MAO) are enzymes responsible for the breakdown of monoamines such as NA, Adr and dopamine. They are involved in the synaptic metabolism of recycled NA - mainly presynaptically but some extraneurally.

Catechol-o-methyltransferases (COMT) are enzymes that breakdown catecholamine such as dopamine, adrenaline and noradrenaline. They are involved in the synaptic metabolism of recycled NA - mainly extraneurally.

Question 5

Describe the pathway of catecholamine biosynthesis

Answer 5

The only difference between cells capable of producing adrenaline from noradrenaline or dopamine is the presence of the later enzymes withint he pathway.

Question 6

What are the dose dependent effects of cocaine?

Answer 6

1. Intense euphoria + craving for more drug
2. Psychological and physical dependence
   * psychotic symptoms, depression, anxiety and fatigue
3. Cardiovascular effect
   * hypertension, tachycardia, coronary vasospasm, dysrhythmia, convulsions

Question 7

How do amphetamines and ephadrines affect NA storage in neurons?

Answer 7

Amphetamines and ephadrines are indirectly acting sympathomimetics that act on the presynaptic storage of NA.

These drugs displace NA from its storage vesicles. This results in the non-exocytotic release of NA into the synapse via catecholamine channels.

This causes increased activation of a- or b-adrenoceptors both peripherally and centrally.

Question 8

What functions are noradrenergic and dopaminergic pathways associated with in the CNS?

Answer 8

Noradrenergic pathways are involved in stimulant, mood, appetite and cardiovascular regulation

Dopamine is considered nothing more than a precursor or NA in the periphery, but in the CNS dopaminergic pathways are involved in:

• Movement - Parkinson’s results from depletion of dopamine in basal ganglia
• Behaviour - Schizophrenia results from changes in dopamin rich areas
• Dependence - Dopaminergic neurons innervate known dependence nuclei in nucleus accumbens and ventral tegmental area
• Pituitary Function - Dopamin results in prolactin secretion

Question 9

Discuss the selectivity of cocaine

Answer 9

Cocaine blocks the reuptake of noradrenaline, dopamine and serotonin at synapses in the CNS

The dopaminergic actions are linked to dependence.

Noradrenergic and serotonergic actions are leads for anti-depressant drugs in development.

Question 10

What is the first line drug treatment of Parkinson’s Disease?

Answer 10

Parkinson’s Disease

Is characterised by the degeneration of dopaminergic pathways

Treatment with:

• L-DOPA + peripheral DOPA Decarboxylase Inhibitor
  
  • Increases the biosynthesis pathway of dopamine in the CNS; while mitigating peripheral side effects of dopamine in the periphery.
• Secondary: MAO B inhibitors, dopamine receptor agonists and muscarinci receptor antagonists

Question 11

What is the first line drug treatment of Huntington’s Disease?

Answer 11

Huntington’s Disease

Is characterised by a deficiency in GABA within the CNS

Treatment:

• GABA agonist Baclofen
• Dopamine antagonists Chloropromazine

Question 12

What are the three divisions of the autonomic nervous system?

Answer 12

1. Sympathetic NS
2. Parasympathetic NS
3. Enteric NS

Question 13

Do autonomic pathways originate in cervical or lower lumbar regions of the spinal cord?

Answer 13

No; there are no autonomic pathways arising from the cervical or lower lumbar enlargements

Question 14

From which regions of the spinal cord do sympathetic and parasympathetic outputs arise respectively?

Answer 14

Sympathetic NS

Thoraco-lumbar spinal segments (but not lower lumbar)

Parasympathetic NS

Craniosacral spinal segments

Question 15

Compare and contrast the position of sympathetic and parasympathetic ganglia

Answer 15

Sympathetic ganglia are typically located more distant to their organs of innervation. Most pre-ganglionic nerves of the sympathetic NS synapse to the paravertebral ganglia (sympathetic chain) that is parallel to the spinal column. These ganglia are the primary source of vasoconstrictor neurons.

Some preganglionic neurons, like pelvic visceral neurons, go through the paravertebral ganglia but do not synapse - instead synapsing on post-ganglionic neurons at **prevertebral ganglia **closer to organ of innervation.These ganglia are the primary source of non-vascular smooth muscle innervation.

Parasympathetic ganglia are generally located closer to or within individual organs.

Question 16

Which level of neurons in the sympathetic, parasympathetic and somatic NS’s are myelinated?

Answer 16

All preganglionic nerves of the autonomic NS are lightly myelinated or unmyelinated.

Postganglionic nerves of the autonomic NS are all unmyelinated.

Somatic motor nerves are variable in myelination

Question 17

Which neurotransmitters are considered ‘classical’ transmitters of the autonomic nervous system?

Provide examples of common ‘non-classical’ transmitters

Answer 17

Classical transmitters applies to the dominant neurotransmitters ACh and NA.

Non classical transmitters include:

• ATP
• Nitric Oxide
• Neuropeptides - Substance P, Neuropeptide Y

Often there is more than one transmitter being released at any one time = co-transmission.

Glutamate and GABA are not significant transmitters in the autonomic nervous system.

Question 18

What is special about autonomic neurotransmission in the organs?

Answer 18

1. No easily identifiable synaptic junctions
2. More than 1 NT release site per axon
3. Receptors can be expressed remotely from the synapse via extrajunctional receptors

Question 19

Where in the spinal cord are preganglionic neurons located within the spinal cord?

Answer 19

Cholinergic preganglionic neurons of the sympathetic nervous system are located in the intermediolateral cell column of spinal cord grey matter.

Question 20

With reference to the concepts of divergence and convergence, discuss the differences in post-ganglionic neurons in the sympathetic NS

Answer 20

Prevertebral ganglion neurons integrate more signals from multiple inputs (particularly the enteric nervous system) and have mor complex dendritic organise to allow greater convergence of information.

Up to 200 paravertebral ganglionic neurons can be activated by one preganglionic neuron - illustrating divergence to produce larger downstream effects.

Question 21

What are the common functions of sympathetic nervous system activation?

Answer 21

Sympathetic activation is characterised by the ‘flight-or-flight’ set of responses; including:

• Increased heart rate
• Increased contractility of the heart
• Increased blood flow to skeletal muscle
• Decreased blood flow to gut
• Decreased gut motility
• Relaxation of airways

Additionally, the preganglionic sympathetics can activate the adrenal gland to release ACh and Adrenaline into the circulation and produce broad systemic activation of adrenoceptors throughout the body

Question 22

Discuss some examples of preganglionic neurons of the parasympathetic NS that arise from the cranial compartment of the nervous system.

Answer 22

Edinger-Westfal Nucleus

Projects to the ciliary ganglion to control sphincter pupillae and ciliary muscle.

Salivatory Nuclei

To submandibular, sphenopalatine and optic ganglia to control lacrimal, salivary, sublingual, nasal and palatine glands

Dorsal Motor Nucleus of Vagus and Nucleus Ambiguss

To microganglia near and on outer surface of thoracic and abdominal organs for visceral functions

Question 23

What is special about autonomic supply to the pelvic organs?

Answer 23

Autonomic supply to pelvic organs is via splanchnic nerves to pelvic ganglia that comprise the **pelvic plexus **overlying or within pelvic organs.

These parasympathetic ganglia have abnormally long axons - leaving them vulnerable to surgically induced injury.

These pelvic ganglia are mixed ganglia - also containing many sympathetic neurons.

Pelvic ganglia are mere relay stations - little integration/few dendrites present

Question 24

Where in the spinal cord would you find cell bodies of preganglionic parasympathetic neurons?

Answer 24

Preganglionic parasympathetic neurons are located laterally within the intermediate grey zone of the sacral spinal cord

Question 25

What are the common features of parasympathetic activation?

Answer 25

Parasympathetic activation invokes a 'rest and digest' set of functions; including: * Decreased heart rate * Decreased contractility of the heart * Increased gut motility * Constriction of airways Compared with sympathetic pathways, parasympathetic have: * lower ratios of pre:post ganglionic neurons (less divergence) * Parasympathetic ganglia are simple relay stations that don't integrate or coordinate information * No equivalent of adrenal gland for systemic activation

Question 26

How can you **_definitively_** distinguish between sympathetic and parasympathetic nerves?

Answer 26

The only unequivocal definition between sympathetic and parasympathetic nerves is the **_location of preganglionic fibres_** Sympathetic: thoracic + lumbar spinal cord Parasympathetic: cranial nuclei + sacral spinal cord Other properties are unreliable and too many exceptions exist to be used as general rules of distinction; e.g.: * Neurotransmitters * Strucutre of ganglions neurons * Physiological effects

Question 27

Describe a typical autonomic reflex

Answer 27

**Visceral afferent (sensory) neurons** provide input to local interneurons and projection neurons (either ascending or efferent) within the spinal and brainstem circuits. Most autonomic reflexes involve the brain **(****supraspinal reflex)**; rather than only the spinal cord**(****spinal reflex)** Lesions that disrupt ascending and descending connections with the brain can cause disruption to reflexes involving: bladder, sexual function, cardiovascular and thermal regulation

Question 28

How is the hypothalamus involved in the coordination of autonomic output?

Answer 28

The hypothalamus initiates and coordinates an appropriate autonomic responses involving: * Fight or flight * Feeding * Thermoregulation * Circadian rhythms * Water balance * Sexual function Hypothalamus compares current situations with biological set points; adjust behavoiur and autonomic function to achieve homeostasis. It **integrates with higher cortical and limbic systems** to produce appropriate responses to emotion, fear, anxiety and motivations.

Question 29

What is the role of the nucleus of the solitary tract in autonomic NS regulation?

Answer 29

The caudal part of the **nucleus of the solitary tract (NTS)** is located in the **medulla**. It is a major **integrative centre for autonomic function** It recieves input from visceral afferents and distributes information to either: 1. local reflexes that control organ/tissue function via preganglionic neurons; or 2. higher cortical and subcortical centres for more complex responses (e.g hypothalamus, thalamus and cortex)

Question 30

What are local anaesthetics? and What classes of local anaesthetics exist?

Answer 30

Local anaesthetics are drugs that reversibly block the conduction of nerve impulses at the axonal membrane via Na+ channel inhibition Local anaesthetics tend to be **_weak bases_** with different onset, duration and toxicity profiles There are three main classes of local anaesthetics: 1. **_Aminoesters_** * **Hydrophilic** mechanism of action * Shorter acting (30-45 min) * Removed by hydrolysis via esterases * e.g. **procaine** 2. **_Aminoamides_** * **Hydrophilic** mechanism of action * Longer acting (hours) * Removed via hepatic metabolism * e.g. **Lignocaine** and **Ropivicaine **(most common in Aus) 3. **_Benzocaine_** * **Hydrophobic** mechanism of action

Question 31

Where is the binding site of local anaesthetics?

Answer 31

Local anaesthetics bind **S6 in transmembrane domain IV** of Na+ channels * This binding site is intracellular - affects the mechanism of action of local anaesthetics able to enter the cell * Hydrophobic (benzocaine) vs Hydrophilic (aminoester and aminoamines) **Toxins** (tetrodotoxin/puffer fish) bind extracellular domains of Na+ channels to cause anaesthetic action - different mode

Question 32

Discuss the differences in sensitivity to local anaesthetics between different types of nerves.

Answer 32

**Smaller nerve fibres are more sensitive** to local anaesthetic effects. Thus sensitivity in: **_sensory \> autonomic \> motor_** The preferential effects on sensory nerves allows sensation to be inhibited without compromising the motor effects of the nervous system - e.g respiratory and cardiac innervation required for survival. In sufficient concentrations, however, widespread motor impairment is likely.

Question 33

Compare the two different mechanisms of local anaesthetic action

Answer 33

There are two mechanisms of local anaesthetic actions: **_Hydrophobic Pathway_** (non use-dependent) The base form of the drug (B) is the predominant form (uncharged) and freely diffuses through the lipid membrane of axons as a hydrophobic molecule. It directly binds to the S6 transmembrane domain and blocks electrical conduction. This pathway is fast acting and non-use-dependent due to the rapid ease of binding. **Benzocaine** is an example **_Hydrophilic Pathway_** (use dependent) The predominant drug form is ionised (BH+) and has difficulty in diffusing through axon membrane. Small proportion is in base form (B) and this is able to diffuse through into the intracellular space. In the intracellular space base form (B) becomes charged again (BH+) and enters the channel to bind S6 - this _requires the channels to be open and being 'used'_. Thus, they are slow acting and use dependent. Examples include **aminoesters and aminoamines**.

Question 34

What are the general properties of local aesthetics?

Answer 34

1. Prevent the propagation of nerve action potentials 2. Small fibres are more sensitive (sensory \> ANS \> motor) 3. Axon membrane (RMP) remains stable/unchanged 4. Effects more pronounced in basic mediums * uncharged species are more active * at physiological p.H 7.4 more ionised forms are present 7. Greater anaesthetic affects if the nerve is firing / being used

Question 35

Discuss local anaesthetic toxicity

Answer 35

Local anaesthetics are generally safe drugs when used by trained physicians. They selectively bind Na+ channels and display reversible binding without nerve damage...but will affect all excitable tissues with Na+ channels. **_proportional [Blood] toxicity_** _Cardiovascular_ * direct myocardial depression * depression of vasomotor centre * hypotension (except cocaine) _CNS_ * excitation (inhibitory fibres first affected) * tremor * convulsion * respiratory arrest **_non-proportional [Blood] toxicity_** _Hypersensitivity/Allergic reactions_ * both to the anaesthetic itself and their stabilising agents

Question 36

Discuss the usefulness of topical local anaesthetics

Answer 36

There are two main forms of topical local anaesthetics: **_Lozenges:_** Generally used for throat drops - contain benzocaine (fast acting, readily diffusable) **_Gels:_** Tend to contain small concentrations of lignocaine. Generally poor absorption across skin (barrier to access) and acidic inflammatory environment inconducive to mechanism of action (ionises the drug - can't diffuse into axon membrane)

Question 37

What are the four stages of general anaesthesia?

Answer 37

**_Stage 1_** * Amnesia * Euphoria **_Stage 2_** * Excitement * Delirium * Resistance to handling **_Stage 3_** * ***Commence surgery *** * Unconsciousness * Regular respiration * Decreasing eye movement **_Stage 4_** * Respiratory arrest * Cardiac depression + arrest

Question 38

Provide examples of general anaesthetic agents

Answer 38

Inhalational: * **Desflurane** * **Sevoflurane** * **Isoflurane** Intravenous * **Propofol** * **Thiopentone**

Question 39

What are the side effects of general anaesthetics?

Answer 39

Respiratory * Impaired ventilation * Depression of respiratory centers * Obstruction of airways * Retention of secretions in airways Cardiovascular * Decreased vasomotor centre function * Depress contractility * Peripheral vasodilation * Cardiac arrhythmias * Inadequate responses to BP or CO changes

Question 40

How do general anaesthetics work?

Answer 40

General anaesthetics depress cortical processing of pain/sensory signals by inducing a loss of consciousness. **_It is not known how general anaesthetics work exactly_** Two leading hypothesises: **_Lipid Theory _** * Anaesthesia is caused by **volume expansion of membrane lipids** (which can be reversed by pressure) that disrupts electrical signalling * There is an intimate **correlation between anaesthetic potency and lipid solubility** **_Receptor Interactions_** * Anaesthetics inhibit a range of excitory receptors (glutamate and NMDA) and enhance effects on inhibitory receptors (GABA + glycine)

Question 41

How can you selectively target receptors and ion channels of the CNS to treat symptoms of epilepsy?

Answer 41

In epilepsy, there is excessive discharge of motor neurons as a result of abnormal inputs from excitatory and inhibitory interneurons Can selectively target use-dependent pathways of the CNS **Reduce excitatory input**: 1. Limit excitatory interneuron activation * **Phenytonin **inhibits Na⁺ channels of these neurons 2. Inhibit T-type Ca²⁺ channels (prevents NT release) from interneurons 3. Inhibit excitatory receptors on motor neurons **Enhance inhibitory input:** 1. Enhance GABA receptor activity * **Benzodiazapines**

Question 42

What is nociceptive pain?

Answer 42

**_Nociceptive pain_** is an **adaptive, high threshold pain** that acts as an early warning system against further damage. Nociceptors are **high threshold receptors** of noxious stimuli - the stimulus must be of high intensity to elicit an action potential response and transmit to the CNS. Nociceptive pain leads to the _perception of pain, autonomic response to pain and withdrawl reflexes_.

Question 43

What neuron fibre types are responsible for conducting nociceptive pain?

Answer 43

Nociceptive pain is conducted via two types of free nerve ending sensory afferents: **_C-fibres: _** * fine diameter (\<1.5 micrometers) * unmyelinated * slow transmission (\<3m/s) * innervate superficial regions of dorsal horn laminae - **regions 1 & 2** **_Ad fibres: _** * thick diameter (1.5-4 micrometers) * myelinated fibres * fast transmission (3-30m/s) * innervate region **1 & 5 of dorsal horn laminae**

Question 44

By what pathway does nociceptive information transmit to the brain/within the CNS?

Answer 44

Primary C-fibre and Ad sensory afferents enter the dorsal horn and synapse onto secondary sensory afferents. These secondary afferents **decussate to the contralateral side** of the spinal cord and run in the **anterolateral tract** to the brain.

Question 45

Can nociceptive primary afferents be stimulated without the experience of pain?

Answer 45

There are local spinal cord interneurons responsible for producing a reflex response to nociceptive afferent fibre activation - meaning there is no brain processing and no pain felt. Thus, nociceptive fibres can be activated without feeling pain.

Question 46

What is inflammatory pain?

Answer 46

Inflammatory pain is an **adaptive, low threshold pain** that promotes injury repair by inducing **avoidance behaviour** in not using body parts due to **pain hypersensitivity**/**tenderness**. Inflammatory structures such as macrophages, mast cells, neutrophils, granulocytes and damaged tissue itself release a range of mediators that target and **sensitise nociceptor ion channels and receptors**. This is **peripheral sensitisation **and leads to **primary** (peripheral) **hyperalgesia **

Question 47

What is the significance of TRPV1?

Answer 47

TRPV1 is a nociceptive transducer involved in the sensation of heat, capsaicin (chillis), acid and chemicals

Question 48

Contrast and compare the concepts of 'hyperalgesia' and 'allodynia'

Answer 48

**_Hyperalgesia_** is an increased response to a normally painful stimulus **_Allodynia_** is a painful response to a normally innocuous stimulus

Question 49

What is the difference between primary and secondary forms of hyperalgesia and allodynnia?

Answer 49

Question 50

Does inferred pain result from primary or secondary hyperalgesia?

Answer 50

Sensitisation of the CNS alters how primary nociceptive afferents are processed in the spinal cord. In the presence of a sustained noxius stimulant in the periphery, s**econdary hyperalgesia throughout levels of the spinal cord can infer pain from a wider area** than where the noxious stimulus actually is

Question 51

What is maladaptive pain?

Answer 51

**Maladaptive pain is maladaptive, low threshold pain that results from disease of the nervous system**. It involves marked neuroimmune responses leading to _peripheral and/or central sensitisation. _ It incorporates **neuropathic pain** and **dysfunctional pain** **Neuropathic pain** results from lesions to the somatosensory system in the periphery and/or CNS **Dysfunctional pain **occurs for no known reason e.g. migraines or neuromyalgia. Pain is both **spontaneous and stimulus dependent**

Question 52

What is pain? How does pain relate to behaviour?

Answer 52

Pain is an **unpleasant sensory and emotional experience** associated with actual or potential tissue damage - or described in terms of such damage **Pain is expressed in behaviour**. Our behaviour os how we express and communicate pain to others (e.g. crying + avoidance); thus, pain has an important effect on behaviour

Question 53

Can pain be modulated in any way?

Answer 53

There is a descending pain modulation pathway that can block/interfere with the transmission of pain related information within the spinal cord. The pathway runs through the anterior cingulate, prefrontal cortex, insula, **periaqueductal gray region **of the brainstem, **RVM **and down the spinal cord onto primary and secondary nociceptive afferents within the spinal cord. This pathway is engaged by inflammation, analgesic drugs and psychophysiological states. * Placebo and nocebo effects can result from this pathway

Question 54

In the pshychobiological model of pain; what are the main domains of experiencing pain?

Answer 54

1. **Nociception** 2. **Injury** - peripheral and central sensitisation 3. **Chemical and structural** - atrophy and opiodergic/dopaminergic dysfunction 4. **Context** - beliefs, expectations, placebo/nocebo 5. **Mood** - depression, anxiety, fear, catastophising 6. **Cognition** - attention, control, re-appraisal

Question 55

What are **b****enzodiazepines **indicated for?

Answer 55

Benzodiazepines are indicated for treatment: * **Epilepsy** * **Anxiety** * **Sleep disorders** * **Premedication** * Sedation for medical procedures * **Acute alcohol withdrawl**

Question 56

What neurotransmitters are implicated as sedative-hypnotic and anxiolytic agents?

Answer 56

**_Sedation-hypnotic and anxiety_** **GABA** * main inhibitory transmitter in the CNS * GABA A ligand-gated receptor primary target **Serotonin** * CNS prejunctional receptors **_Anxiety_** **Noradrenaline** **Neuropeptide Y** * target of future therapies **_Sedation_** **Histamine** * H1 receptor antagonists are sedative

Question 57

What is anxiety?

Answer 57

**_Anxiety is the manifestation of "fear responses" in an anticipatory manner, independent of external events_** It is associated with: * marked sweating * tachycardia * chest pains * trembling * choking Beta-adrenoceptor antagonists provide some symptomatic relief to periphery symptoms but have little effect on the CNS symptoms. Need sedative-hypnotic and anxiolytic agents.

Question 58

What are the four main clinically recognised anxiety disorders?

Answer 58

1. Generalised anxiety states * excessive anxiety lacking any clear reason or focus 2. Panic disorder * overwhelming fear in association with somatic signs 3. Phobias * Strong fears of specific things/situations 4. Post-traumatic stress disorder

Question 59

Profile barbituate pharmacology

Answer 59

Barbituates are general depressants that produce all levels of CNS depression -\> mild sedation, surgical anaesthesia, coma and death. It is a directly gating or channel opening agent of GABA-A receptors: it **_prolongs the opening of these Cl_^-_ channels in response to GABA_**_._ ***I******ncreases both the sensitivity to GABA and maximum response of the GABA-A receptor*** It is an effective compound; but is: * **exceedingly toxic** * low therapeutic index * inducts liver enzymes * abrupt withdrawl causes death * **highly addictive** Is no longer prescribed for anxiolytics/hypnotics due to danger of overdosing, but continues to be used in controlled situations as an _anaesthetic_ and _anti-convulsant_.

Question 60

Profile the pharmacology of bemzodiazepines

Answer 60

Benzodiazepines are general depressants. Compared with barbituates, benzodiazepines demonstrate: * **less depression of respiratory and cardiovascular centres** * **less dependence** * **safety in overdose** due to the way they affect the GABA-A receptors Benzodiazepines are **allosteric modulators** of the GABA-A receptor. They facilitate the opening of Cl^- channels -\> i**ncreasing the frequency of channel opening**, but not changing the mean open time/conductance of Cl^-. _Benzodiazepines increase the sensitivity of the receptor with no change in maximum response._ **Disadvantages of benzodiazepines:** * Interactions with alcohol, anti-histamines and barbituates * Long lasting hang-over effects (drowsiness etc) * Withdrawls symptoms common * Dependence (but less than barbituates) * nausea, tremor,anxiety, depression etc. * Tolerance development * need gradual dose escalation

Question 61

What are the three different pathways of allosteric modulation

Answer 61

1. Modulation of orthosteric ligand activity 2. Modulation of orthosteric ligand efficacy 3. Modulation of receptor activation level

Question 62

What are the advantages of allosteric modulators?

Answer 62

1. ***_Ceiling of effect of inhibitors_*** * increases therapeutic window 2. **Positive modulation of endogenous agonist** effect rather than continuous effect of exogenous agonist * physiological regulation continues 3. Great r**eceptor subtype selectivity** possible

Question 63

What are the symptomatic relief effects of benzodiazepines? What adverse effects can occur?

Answer 63

Benzodiazepines elicit: * **Sedation and induction of sleep** * reduce time to fall asleep * increase duration of sleep * **Reduction of anxiety and aggression** * **Reduction of muscle tone** * anti-convulsant (but reduces coordination) * **Obliterate memory** * used as premedicant to surgery etc. Side effects of benzodiazepines: * **Drowsiness** * **Confusion** * **Impaired consciousness** These effects contribute to the 'hang-over' experienced after taking benzodiazepines

Question 64

What factors are considered when determining the type (short acting vs long acting) of benzodiazepine? clue: use as a hypnotic or anxiolytic?

Answer 64

Question 65

Compare and contrast the effects of barbituates and benzodiazepines on GABA potency and efficacy

Answer 65

Both compounds potentiate the effect of GABA to GABA-A receptors. **_Benzodiazepines (increased potency)_** * increase the frequency of the chloride ion channel opening at the GABA-A receptor * Pharmacodynamics: ***_This increases the potency of GABA _*** * less GABA dosage required because the GABA present has elevated affinity for the GABA-A receptor **_Barbituates (increased efficacy)_** * Barbiturates produce their pharmacological effects by increasing the duration of chloride ion channel opening at the GABA-A receptor * Pharmacodynamics: **This increases the efficacy of GABA**

Question 66

Why are benzodiazepines safer when overdosing compared to barbituates?

Answer 66

The **direct gating or opening of the chloride ion channel** is the reason for the **increased toxicity of barbiturates** compared to benzodiazepines in overdose. **Benzodiazepines** increase the frequency of the chloride ion channel opening at the GABA-A receptor. As an allosteric modulator of the receptor, there is a **functional ceiling of effect that benzodiaepines reach** -\> unable to produce more effect/harm above this level.

Question 67

Discuss some non-benzodiazepine hypnotics

Answer 67

**_Zolpidem_** * short term treatment of insomnia * short action of duration (t_1/2= 4 hrs) * binds same benzodiazepine site **_Zopiclone_** * short term treatment of insomnia * profile similar to benzodiazepine although structurally unrelated * Binds at a seperate site to BDZ at the GABA-A receptor

Question 68

Discuss a non-benzodiazepine anxiolytic

Answer 68

**_Buspirone_** * partial agonist at 5HT-_1A receptors * these are inhibitory autoreceptors regulating non-serotonergic nerve transmitter release * slow onset (2 weeks) * little dependence * side effects * nausea, diziness, headache

Question 69

What is the difference between drug dependence and drug abuse?

Answer 69

**_Drug Dependence_** State where drug use becomes compulsive taking precedence over other needs arises because of **_Drug Abuse_** Use of illicit substances (or illicit use of legal substances) characterised by recurrent and clinically significant adverse consequenses.

Question 70

What circuits are involved in drug abuse and addiction?

Answer 70

**_Reward / Salience_** * ***nucleus accumbens*** * ventral pallidium **_Inhibitory control_** * prefrontal cortex * anterior cingulate gyrus **_Memory and learning_** * hippocampus * amygdala **_Motivation / drive_** * orbitofrontal cortex * subcallosal cortex

Question 71

How do drugs of dependence cause dependence?

Answer 71

They ***_increase dopamine in the nucleus accumbens_*** There are several key transmitters that modulate dopaminergic transmission: * Acetylcholine, Serotonin (5-HT), Noradrenaline * GABA, Glutamate * Opioids

Question 72

Why do people take drugs of dependence?

Answer 72

**_To feel good_** Experience novel feelings, sensations, experiences **_To feel better_** Lessen anxieties, worries, fears, depression, hopelesness Note: the same area of the brain involved in dependence are deficient in transmission in states of depression

Question 73

Discuss illicit **amphetamines **as a CNS stimulant

Answer 73

Amphetamines are indirectly acting sympathomimetics that **displace DA, 5-HT or NA** from vesicles in the pre-synaptic cell and **elevate synaptic levels of these NT** via non-exocytotic monoamine channels ***Dependence relates to increasing DA levels in the nucleus accumbens *** _Effects as a CNS stimulant:_ Vary with mood, personality, environment and dose * mood elevation, euphoria * increase locomotor activity * stereotypic behaviour to individual Improved physical performance and 'perceived mental' performance Appetite suppressant from 5-HT effect **_Overdose_** * Stimulant effects: tremors, confusion, dizziness, time passes quickly * Cardiac effects: hyperthermia, tachycardia, increased blood pressure, vascular collapse - death * Psychotic effects: amphetamine psychosis - hallucinations

Question 74

Discuss illicit ecstasy as CNS stimulant and hallucinogenic

Answer 74

Ecstasy / MNDA is a stimulant and hallucinogenic that increases the release of dopamine and serotonin (indirectly acting sympathomimetic) * are less effective than amphetamines and LSD * feelings of love, closeness and empathy Adverse effects: * Psychological dependence * Degeneration of 5-HT and DA neurons * disrupts thermoregulation * affects mood, sleep, memory and appetite

Question 75

Discuss illicit LSD as a Hallucinogen

Answer 75

***LSD is a 5-HT₂ receptor agonist*** that results in severe hallucinations Hallucinogenic effects result from ***_activation of 5-HT₂autoreceptors on 5-HT neurones in Raphe_*** The hallucinations involve confusement of sensory modalities leading to **_visual, auditory & tactile hallucinations_** **Less dependence** than other drugs -\> the experience is so disturbing that adversive **LSD displayes tolerance** -\> need more to achieve same effects in subsequent use * also demonstrates cross-tolerance with other psychomimetics -\> need more of them while concurrently on LSD

Question 76

Discuss the effects of caffeine as a CNS stimulant

Answer 76

Caffeine is an **adenosine antagonist** and **phosphodiesterases inhibitor**; resulting in elevated levels of NA, DA and 5-HT **_Increases alertness by stimulating mental activity_** * High doses = anxiety, tension & tremors No strong dependence effect in animals -\> the social aspect of coffee drinking is the factor in humans

Question 77

Describe the effects of Ethanol as a CNS depressant

Answer 77

Ethanol is CNS depressant that acts on inhibitory neural pathways including: * **Inhibit Ca²⁺channel opening** * **Enhance GABA / GABA-A receptor activity** * I**nhibt glutamate NMDA channels** Effects: * Increased self confidence, euphoria, aggression * Loss of motor coordination and speech * Liver damages, foetal impairment etc Ethanol use -\> **marked tolerance** (switches on liver enzymes) **Physical dependance**

Question 78

Discuss **delta-9 THC **as a CNS depressant

Answer 78

**delta-9 THC **is a CNS depressant that acts at cannabinoid receptors of the CNS Cannabinoid receptor activation results in **inhibition of adenylate cyclase** -\> results in **_inhibition of neural transmission_** **_CB1-central_** * Impaired short term memory * Impaired motor coordination * Catalepsy * Analgesia * Anti-emetic * Increased appetite **_CB2-peripheral_** * Tachycardia, sympathetic * Vasodilatation * Reduced intraocular pressure * Bronchodilatation

Question 79

Describe the generational development of anti-depressant drugs (for unipolar depression)

Answer 79

**_1st Generation_** * Tricyclic antidepressants * MAO inhibitors **_2nd Generation_** * Selective Serotonin uptake inhibitors (SSRIs) * Selective Serotonin/Noradrenaline uptake inhibitors (SSNRIs) **_3rd Generation_** * Novel monoaminergic drugs * Non-monoaminergic drugs

Question 80

Discuss tricyclic antidepressants as a treatment for depression

Answer 80

TCAs ***_inhibit neuronal uptake of noradrenaline and serotonin_*** This is achieved by competitively antagonising a-adrenoreceptors and serotonin receptors involved in neural re-uptake. The drugs have **poor selectivity** and can affect other receptors including muscarininc and histamine receptors **Clinical effects took weeks to develop =slow; ** despite pharmacologically effects manifesting in hours -\> patients lost complience Has a **narrow therapeutic window** Side effects: * Autonomic / CV side effects * Weight gain * Sedation * Seizures

Question 81

Discuss MAO inhibitors as an antidepressant

Answer 81

MAO inhibitors inhibit the MAO enzymes responsible for degrading 5-HT, NA and DA This increases levels of these monamines **This can be either irreversible or reversible** **Irreversible** * 'Cheese reaction' * foods containing the amine **tyramine** cause a hypertensive crisis due poor metabolism of it **Reversible** * Less likely to cause cheese reaction * Side effects: postural hypotension, dizziness, nausea

Question 82

Discuss selective serotonin reuptake inhibitors as a treatment of depression (SSRIs)

Answer 82

Demonstrate **selectivity** with respect to 5-HT over noradrenaline inhibiting re-uptake. **Large therapeutic window** They are less likely than TCAs to cause anticholinergic side effects and are less dangerous in overdose. In contrast to MAOIs, they do not cause ‘cheese reactions'. Side effects: * Nausea, insomnia, agitation, weight change, loss of libido

Question 83

Illustrate the progression in anti-depressant development throughout recent history

Answer 83